title: Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker.
abstract: Hematopoietic tissues in acute myeloid leukemia (AML) patients contain both leukemia stem cells (LSC) and residual normal hematopoietic stem cells (HSC). The ability to prospectively separate residual HSC from LSC would enable important scientific and clinical investigation including the possibility of purged autologous hematopoietic cell transplants. We report here the identification of TIM3 as an AML stem cell surface marker more highly expressed on multiple specimens of AML LSC than on normal bone marrow HSC. TIM3 expression was detected in all cytogenetic subgroups of AML, but was significantly higher in AML-associated with core binding factor translocations or mutations in CEBPA. By assessing engraftment in NOD/SCID/IL2Rγ-null mice, we determined that HSC function resides predominantly in the TIM3-negative fraction of normal bone marrow, whereas LSC function from multiple AML specimens resides predominantly in the TIM3-positive compartment. Significantly, differential TIM3 expression enabled the prospective separation of HSC from LSC in the majority of AML specimens with detectable residual HSC function.
authors.affiliation: Program in Cancer Biology, Cancer Center, Institute for Stem Cell Biology and Regenerative Medicine, Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Jan
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Adriel C
authors.initials: AC
authors.lastname: Cha
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002469:Cell Separation / Q000379:methods*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation
chemical_list: D014408:Biomarkers, Tumor; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins